Altered Chloride homeostasis in Reactive plasticity upOn BrAin Trauma

创伤性脑损伤是导致永久性残疾的主要损伤相关原因，也是欧洲第三大死亡原因。在世界范围内，每年有超过1000万人受到影响。创伤后癫痫是年轻人新发癫痫的最常见原因;在脑穿透伤后，发展为癫痫的可能性超过50%。30%至40%的创伤后癫痫患者的症状无法用现有药物完全控制。此外，目前可用的抗癫痫药物的不必要治疗可能会损害脑外伤后的神经康复。很明显，这一领域迫切需要新的治疗相关的目标。为了找到它们，我们需要详细了解脑外伤的发病机制。在这项计划中，五个欧洲研究小组将致力于一个共同的目标：揭示创伤诱导的皮层抑制性神经传递变化的机制和影响。我们合作者的初步结果提出了一个工作假设，即脑创伤后抑制性神经传递改变的主要成分是参与神经元氯离子转运的蛋白质的功能。神经元氯调节的随后异常不仅扰乱抑制信号，而且似乎对创伤后神经元的存活和增殖至关重要，导致神经元网络的活性改变。因此，神经元中氯离子转运功能障碍的多方面影响使其成为一个特别有前途的目标，具有很强的潜力，可用于创新治疗策略，以改善未来脑外伤患者的康复。

Traumatic brain injuries are the main injury-related causes of permanent disability, and arethe third leading cause of mortality in Europe. Worldwide, more than 10 million people areaffected every year. Post-traumatic epilepsy is the most common cause of new-onsetepilepsy in young adults; following penetrating brain wounds, the likelihood of developingepilepsy is more than 50%. 30 to 40% of patients with post-traumatic epilepsy have seizuresthat are incompletely controlled with currently available medication. Moreover, unnecessarytreatment with currently available antiepileptic drugs may then impair neurorehabilitation afterbrain trauma. It is evident that this field desperately needs new therapeutically relevanttargets. In order to find them, we need to understand in detail the mechanisms engagedupon brain trauma. In this proposal, five European groups, with expertise ranging fromcellular to systems Neuroscience, will pursue a common aim: to disclose the mechanismsand impact of trauma-induced changes in inhibitory neurotransmission in the cortex.Preliminary results from our collaborators suggest a working hypothesis in which a majorcomponent of altered inhibitory neurotransmission upon brain trauma is themalfunction of proteins involved in chloride transport in neurons. Subsequentabnormalities in neuronal chloride regulation not only perturb inhibitory signals, but alsoappear to be crucial for post-traumatic neuronal survival and proliferation, leading to alteredactivity of neuronal networks. Thus, the multifaceted impact of chloride transport malfunctionin neurons makes it a particularly promising target with strong potential for innovativetherapeutic strategies to improve rehabilitation of brain trauma patients in the future.